Molecular modeling of the three-dimensional structure of GLP-1R and its interactions with several agonists.
Glucagon-like peptide-1 receptor (GLP-1R) is a promising molecular target for developing drugs treating type 2 diabetes. We have predicted the complete three-dimensional structure of GLP-1R and the binding modes of several GLP-1R agonists, including GLP-1, Boc5, and Cpd1, through a combination of homology modeling, molecular docking, and long-time molecular dynamics simulation on a lipid bilayer. Our model can reasonably interpret the results of a number of mutation experiments regarding GLP-1R as well as the successful modification to GLP-1 by Liraglutide. Our model is also validated by a recently revealed crystal structure of the extracellular domain of GLP-1R. An activation mechanism of GLP-1R agonists is proposed based on the principal component analysis and normal mode analysis on our predicted GLP-1R structure. Before the complete structure of GLP-1R is determined through experimental means, our model may serve as a valuable reference for characterizing the interactions between GLP-1R and its agonists.
Lin
Fu
F
State Key Laboratory of Bioorganic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, People's Republic of China.
Wang
Renxiao
R
D000818:Animals; D003198:Computer Simulation; D003503:Cyclobutanes / Q000737:chemistry* / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D008958:Models, Molecular; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists*
C533559:Boc5 compound; D003503:Cyclobutanes; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D008051:Lipid Bilayers; D018027:Receptors, Glucagon